Vasodilating and antihypertensive compositions and methods of effecting vasodilation and treating hypertension utilizing 2-amino-4H pyrane as the active agent

ABSTRACT

2-Amino-4 H-pyrane derivatives of the formula ##SPC1## 
     Wherein 
     R 1  and R 2  are the same of different and each is hydrogen or straight- or branched-chain alkyl; 
     R 3  is straight- or branched-chain alkyl, phenyl or --COOR&#39; wherein R&#39; is a straight, branched or cyclic saturated or unsaturated aliphatic hydrocarbon; 
     R 4  is straight, branched or cyclic alkyl or alkenyl, aryl unsubstituted or substituted by 1, 2 or 3 of the same or different substituents selected from the group consisting of akyl, alkoxy, halogen, nitro, cyao, trifluoromethyl, carbalkoxy, and --SO n  alkyl wherein n is 0, 1 or 2, or 
     R 4  is naphthyl, quinolyl, pyridyl, thienyl or furyl unsubstituted or substituted by alkyl, alkoxy or halogen; 
     R 5  is straight, branched or cyclic alkyl or --OR&#34;  wherein R&#34; is a straight, branched or cyclic hydrocarbon or said hydrocarbon interrupted by 1 or 2 oxygen atoms; and 
     R 6  is hydrogen or alkyl; 
     Are useful for their strong coronary action and as antihypertensive agents. 
     This is a division of parent application Ser. No. 375,809, filed July 2, 1973 now U.S. Pat. No. 3,897,462, issued on July 29, 1975.

The present invention relates to 2-amino-4 H-pyrane derivates, toprocesses for their production, to pharmaceutical compositions embodyingsaid compounds as the active ingredient and to their use as vasodilatorsand antihypertensive agents.

It has already been disclosed that the reaction of α,β-unsaturatedcarbonyl compounds with enamines leads to 2,3-dihydro-4 H-pyranes, forexample: ##SPC2##

(compare I. W. Lewis, P. L. Myers, M. I. Readhead, J. Chem. Soc. C,1970, 771).

Inamines react similarly (J. Ficini, A. Krief, Tetrahedron Letters 1969,1427).

Hitherto, nothing has been disclosed regarding a possiblecirculation-influencing effect of these 4 H-pyranes.

It has furthermore been disclosed that the reaction of4-nitrobenzylidene-acetylactone with potassium cyanide in an alkalinemedium yields 3-acetyl-5-amino-2-methyl-4-(p-nitrophenyl) furane (seeequation): ##SPC3##

(compare I. P. Sword, J. Chem. Soc. C, 1970, 1916).

More particularly, the present invention is concerned with 2-amino-4H-pyrane derivatives of the formula: ##SPC4##

Wherein

R¹ and R² are the same or different and are each hydrogen or straight-or branched-chain alkyl, especially lower alkyl;

R³ is straight- or branched-chain alkyl, especially lower alkyl, phenylor --COOR' wherein R' is a straight, branched or cyclic saturated orunsaturated aliphatic hydrocarbon, especially lower alkyl, loweralkenyl, lower alkynyl, cycloalkyl of 3 to 7 carbon atoms orcycloalkenyl of 3 to 7 carbon atoms;

R⁴ is straight, branched or cyclic alkyl or alkenyl, especially loweralkyl, lower alkenyl, cycloalkyl of 3 to 7 carbon atoms or cycloalkenylof 3 to 7 carbon atoms, aryl, especially phenyl, unsubstituted orsubstituted by 1, 2 or 3 of the same or different substituents selectedfrom the group consisting of alkyl, especially lower alkyl, alkoxy,especially lower alkoxy, halogen, nitro, cyano, trifluoromethyl,carbalkoxy, especially carb(lower alkoxy), and --SO_(n) alkyl,especially lower alkyl, wherein n is 0, 1 or 2, or

R⁴ is naphthyl, quinolyl, pyridyl, thenyl or furyl unsubstituted orsubstituted by alkyl, especially lower alkyl, alkoxy, especially loweralkoxy, or halogen;

R⁵ is straight, branched or cyclic alkyl, especially straight- orbranched-chain lower alkyl, or cycloalkyl of 3 to 7 carbon atoms, or--OR" wherein R" is a straight, branched or cyclic hydrocarbon, or saidhydrocarbons interrupted by 1 or 2 oxygen atoms, especially straight- orbranched-chain lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl of3 to 7 carbon atoms, cycloalkenyl of 3 to 7 carbon atoms, or said loweralkyl, lower alkenyl, lower alkynyl, cycloalkyl of 3 to 7 carbon atoms,or cycloalkenyl of 3 to 7 carbon atoms interrupted by 1 or 2 oxygenatoms; and

R⁶ is hydrogen or alkyl, especially lower alkyl.

The 2-amino-4 H-pyrane derivatives of the present invention areparticularly useful because they exhibit a strong coronary action,particularly a vasodilating action, as well as a good antihypertensiveeffect. The compounds of the present invention may be produced byreacting an α,β-unsaturated dicarbonyl compound of the formula ##STR1##wherein R⁴, R⁵ and R⁶ are as above defined,

a. with an inamine of the formula ##STR2## wherein R¹, R² and R³ are asabove defined except that R³ is not --COOR'

in an inert organic solvent at a temperature of from about 10° C toabout 200° C, to produce a compound wherein R³ is other than --COOR', or

b. with a cyanoacetic acid ester of the formula

    R.sup.3 --CH.sub.2 --CN                                    IV

wherein R³ is --COOR' wherein R' is as above defined,

in an inert organic solvent at a temperature of from about 10° C to 200°C. to produce a compound wherein R³ is --COOR'

wherein R' is as above defined,

and recovering the compound produced.

The two forms (a) and (b) of the process according to the invention arereferred to throughout this specification as Process Variants (a) and(b).

The compounds according to the invention, of the general formula I, aredistinguished by a long-lasting strong vasodilating action. Hitherto, nopharmaceutical action of such 2-amino-4 H-pyrane derivatives has beendisclosed. The compounds according to the invention represent new agentsfor the treatment of circulatory illnesses and are hence an enrichmentof pharmacy.

If 2'-trifluoromethylbenzylideneacetoacetic acid ethyl ester and1-N,N-diethylaminopropine are used as starting compounds, the course ofthe reaction can be represented by the following equation:

Process Variant (a): ##SPC5##

If 3'-nitrobenzylideneacetoacetic acid methyl ester and cyanoacetic acidethyl ester are used as starting compounds, the following equationapplies:

Process Variant (b): ##SPC6##

According to one embodiment of the present invention

R¹ and R² are the same or different and each are alkyl of 1 to 4 carbonatoms;

R³ is straight- or branched-chain alkyl of 1 to 4 carbon atoms, phenylor --COOR' wherein R' is straight- or branched-chain alkyl of 1 to 5carbon atoms, straight- or branched-chain alkenyl of 2 to 5 carbonatoms, straight- or branched-chain alkynyl of 2 to 5 carbon atoms,cycloalkyl of 3 to 5 carbon atoms, or cycloalkenyl of 3 to 5 carbonatoms;

R⁴ is straight- or branched-chain alkyl of 1 to 6 carbon atoms,cycloalkyl of 3 to 6 carbon atoms, phenyl unsubstituted or substitutedor substituted by 1 or 2 of the same or different substituents selectedfrom the group consisting of alkyl of 1 to 4 carbon atoms, alkoxy of 1to 4 carbon atoms, halogen (especially chloro or bromo), nitro, cyano,trifluoromethyl, carbalkoxy of 1 to 4 carbon atoms in the alkoxy moietyand --SO_(n) alkyl wherein the alkyl moiety is of 1 to 4 carbon atomsand n is 0 or 2, or naphthyl, pyridyl, thenyl or furyl unsubstituted orsubstituted by alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbonatoms or halogen;

R⁵ is straight- or branched-chain alkyl of 1 to 4 carbon atoms or --OR"wherein R" is straight- or branched-chain alkyl of 1 to 5 carbon atoms,straight- or branched-chain alkenyl of 2 to 5 carbon atoms, straight- orbranched-chain alkynyl of 2 to 5 carbon atoms, cycloalkyl of 3 to 5carbon atoms, cycloalkenyl of 3 to 5 carbon atoms, or straight- orbranched-chain alkyl of 1 to 5 carbon atoms or alkenyl of 2 to 5 carbonatoms interrupted by 1 oxygen atom; and

R⁶ is hydrogen or alkyl of 1 to 4 carbon atoms.

According to another embodiment of the present invention

R¹ and R² are the same or different and each are hydrogen, methyl orethyl;

R³ is methyl, ethyl, phenyl or --COOR' wherein R' is methyl, ethyl orallyl;

R⁴ is methyl, phenyl unsubstituted or substituted by nitro, cyano,trifluoromethyl, chloro, methyl, carbethoxy, 1 to 3 methoxy moieties,nitro and methoxy, nitro and trifluoromethyl, nitro and thiomethyl, ornitro and chloro, or

R⁴ is naphthyl, pyridyl, quinolyl, furyl or thenyl;

R⁵ is --OR" wherein R" is methyl, ethyl, propyl, allyl or cyclohexyl;and

R⁶ is methyl or ethyl.

According to another embodiment of the present invention

R¹ and R² are the same or different and each are hydrogen, methyl orethyl;

R³ is methyl, carbomethoxy, or carbethoxy;

R⁴ is methyl, phenyl, unsubstituted or substituted by nitro, chloro,trifluoromethyl, methyl, methoxy, cyano, carbethoxy or nitro and chloro;or

R⁴ is naphthyl, furyl or thenyl;

R⁵ is methoxy, ethoxy, or propoxy; and

R⁶ is methyl.

The α,β-unsaturated dicarbonyl compounds of general formula II are usedas starting compounds in the process according to the invention arealready known or can be manufactured according to known methods (Org.Reactions XV, 204 and thereafter (1967)).

Representative α,β-unsaturated dicarbonyl compounds include:

Benzylideneacetoacetic acid methyl ester,

ethylideneacetoacetic acid methyl ester,

isopropylideneacetoacetic acid methyl ester,

2'-nitrobenzylideneacetoacetic acid methyl ester,

2'-nitrobenzylideneacetylacetone,

benzylideneacetylacetone,

3'-nitrobenzylideneacetoacetic acid methyl ester,

3'-nitrobenzylideneacetoacetic acid propargyl ester,

3'-nitrobenzylideneacetoacetic acid allyl ester,

3'-nitrobenzylideneacetoacetic acid β-methoxyethyl ester,

3'-nitrobenzylideneacetoacetic acid β-ethoxyethyl ester,

3'-nitrobenzylideneacetoacetic acid isopropyl ester,

3'-nitrobenzylideneacetylactone,

4'-nitrobenzylideneacetylactone,

4'-nitrobenzylideneacetoacetic acid β-propoxyethyl ester,

4'-nitrobenzylideneacetoacetic acid n-propyl ester,3'-nitro-6'-chlorobenzylideneacetoacetic acid methyl ester,

2'-cyanobenzylideneacetoacetic acid methyl ester,

2'-cyanobenzylideneacetoacetic acid methyl ester,

2'-cyanobenzylideneacetoacetic acid ethyl ester,

2'-cyanobenzylidenepropionylactic acid ethyl ester,

3'-cyanobenzylideneacetoacetic acid methyl ester,

3'-nitro-4'-chlorobenzylideneacetylacetone,

3'-nitro-4'-chlorobenzylideneacetoacetic acid t-butyl ester,

3'-nitro-4'-chlorobenzylideneacetoacetic acid methyl ester,

2'-nitro-4'-methoxybenzylideneacetoacetic acid methyl ester,

2'-cyano-4'-methylbenzylideneacetoacetic acid ethyl ester,

2'-methylmercaptobenzylideneacetoacetic acid isopropyl ester,

2'-sulphonylmethylbenzylideneacetoacetic acid ethyl ester,

2'-sulphonylbenzylidenemethylacetoacetic acid allyl ester,

4-sulphonylmethylbenzylideneacetoacetic acid ethyl ester,

(1'-naphthylidene)-acetoacetic acid methyl ester,

(1'-naphthylidene)-acetoacetic acid ethyl ester,

(2'-naphthylidene)-acetoacetic acid ethyl ester,

(2'-ethoxy-1'-naphthylidene)-acetoacetic acid methyl ester,

(2'-methoxy-1'-naphthylidene)-acetoacetic acid ethyl ester,

5'-bromo-(1'-naphthylidene)-acetoacetic acid methyl ester,

(2'-quinolyl)-methylideneacetoacetic acid methyl ester,

(4'-quinolyl)-methylideneacetoacetic acid ethyl ester,

(8'-quinolyl)-methylideneacetoacetic acid ethyl ester,

α-pyridylmethylideneacetoacetic acid methyl ester,

α-pyridylmethylideneacetoacetic acid methyl ester,

α-pyridylmethylideneacetoacetic acid ethyl ester,

α-pyridylmethylideneacetoacetic acid allyl ester,

α-pyridylmethylideneacetoacetic acid cyclohexyl ester,

β-pyridylmethylideneacetoacetic acid β-methoxyethyl ester,

γ-pyridylmethylideneacetoacetic acid methyl ester,

6-methyl-α-pyridylmethylideneacetoacetic acid ethyl ester,

(2'-thenyl)-methylideneacetoacetic acid ethyl ester,

(2'-furyl)-methylideneacetoacetic acid allyl ester,

3'-nitrobenzylidenepropionylacetic acid ethyl ester,

α-pyridylmethylidenepropionylacetic acid ethyl ester,

α-pyridylmethylidenepropionylacetic acid methyl ester,

α-pyridylmethylideneacetylactone-2'-, 3'- and 4'-methoxybenzylideneacetoacetic acid ethyl esters,

2'-, 3'- and 4'-methoxybenzylideneacetylacetone,

2'-methoxybenzylideneacetoacetic acid allyl ester,

2'-methoxybenzylidenacetoacetic acid allyl ester,

2'-methoxybenzylideneacetoacetic acid propargyl ester,

2'-methoxybenzylideneacetoacetic acid β-methoxyethyl ester,

2'-isopropoxybenzylideneacetoacetic acid ethyl ester,

3'-butoxybenzylideneacetoacetic acid methyl ester,

3',4',5'-trimethoxybenzylideneacetoacetic acid allyl estester,

2'-methylbenzylidenepropionylacetic acid methyl ester,

2'-,3'- and 4'-methylbenzylideneacetoacetic acid ethyl esters,

2'-methylbenzylideneacetoacetic acid β-methoxyethyl ester,

2'-methylbenzylideneacetoacetic acid β-propoxyethyl ester,

2'-methylbenzylideneacetoacetone,

3',4'-dimethoxy-5'-bromobenzylideneacetoacetic acid ethyl ester,

2'-,3'- and 4'-chloro/bromo/fluorobenzylideneacetoacetic acid ethylesters,

2'-fluorobenzylideneacetoacetic acid methyl ester,

3'-chlorobenzylideneacetylacetone,

3'-chlorobenzylidenepropionylacetic acid ethyl ester,

3'-chlorobenzylideneacetoacetic acid ethyl ester,

2'-chlorobenzylideneacetoacetic acid allyl ester,

2'-,3'- and 4'-trifluoromethylbenzylideneacetoacetic acid isopropylester,

3'-trifluoromethylbenzylideneacetoacetic acid methyl ester,

2'-carboethoxybenzylideneacetoacetic acid ethyl ester,

3'-carboxymethylbenzylideneacetoacetic acid methyl ester and

4'-carboxymethylbenzylideneacetoacetic acid allyl ester.

The inamines of formula III are used as starting compounds in ProcessVarient (a) according to the invention are already known or can bemanufactured according to known methods (H. G. Viehe, M. Reinstein, Ang.Chem. 76, 537 (1964)).

Representative inamines include:

1-Dimethylamino-2-phenylacetylene,

1-diethylamino-2-phenylacetylene,

1-dimethylamino-3,3-dimethylbut-1-ine,

1-diethylaminoprop-1-ine,

1-diethylaminobut-1-ine and

1-diethylaminohex-1-ine.

The cyanoacetic acid esters of formula IV used as starting materials inProcess Variant (b) according to the invention are already known(Inglis, Org. Synth. Coll., Vol. 1, 249 (1932)).

Representative cyanoacetic acid esters include:

cyanoacetic acid ethyl ester,

cyanoacetic acid methyl ester,

cyanoacetic acid propyl ester,

cyanoacetic acid isopropyl ester,

cyanoacetic acid butyl ester,

cyanoacetic acid allyl ester,

cyanoacetic acid propargyl ester and

cyanoacetic acid β-methoxyethyl ester.

Generally all inert organic solvents can be used as a solvent in theabove process. Such solvents include, for example, alcohols (such asmethanol, ethanol and propanol), ethers (such as diozane and diethylether) and hydrocarbons (such as cyclohexane, benzene, toluene andxylene). Preferably, according to Process Variant (a), toluene is used,and according to Process Variant (b), ethanol is used.

While the reaction temperatures can be varied over a substantial range(from about 10° to about 200° C) as indicated above, the preferredtemperature range is between about 20° and about 180° C, and especiallyat about the boiling point of the solvent.

Process Variant (b) is preferably carried out in the presence of a basiccondensation catalyst such as an organic base; for example, piperidine.

In carrying out the process of the present invention the startingmaterials are preferably reacted in substantially molar proportions.

Representative 2-amino-4 H-pyranes according to the present inventioninclude:

a. 2-Amino-6-methyl-4-(2'-nitrophenyl)-4 H-pyrane-3,5-dicarboxylic aciddiethyl ester.

b. 2-Amino-6-methyl-4-(2'-nitrophenyl)-4 H-pyrane-3,5-dicarboxylic acid3-ethyl ester 5-methyl ester.

c. 2-Amino-6-ethyl-4-(3'-nitrophenyl)-4 H-pyrane-3,5-dicarboxylic aciddiethyl ester.

d. 2-Amino-6-methyl-4-(3'-nitro-6'-methoxyphenyl)-4H-pyrane-3,5-dicarboxylic acid diethyl ester.

e. 2-Amino-6-methyl-4-(2'-trifluoromethyl-4'-nitrophenyl)-4H-pyrane-3,5-dicarboxylic acid 3-ethyl ester-5-methyl ester.

f.2-Amino-6-methyl-4-(3'-nitro-6'-methylmercaptophenyl)-3,5-dicarboxylicacid dimethyl ester.

g. 2-Amino-6-methyl-4-(3'-cyanophenyl)-4 H-pyrane-3,5-dicarboxylic acid3-allyl ester-5 ethyl ester.

h. 2-Amino-6-methyl-4-(3'-nitrophenyl)-4 H-pyrane-3,5-dicarboxylic acid3-ethyl ester-5-cyclohexyl ester.

i. 2-Dimethylamino-3-methyl-6-ethyl-4-(3'-carbethoxyphenyl)-4H-pyrane-5-carboxylic acid ethyl ester.

k. 2-Diethylamino-3-ethyl-6-methyl-4-(α-pyridyl)-4 H-pyrane-5-carboxylicacid isopropyl ester.

l. 2-Dimethylamino-3-methyl-6-ethyl-4-(2'-cyanophenyl)-4H-pyrane-5-carboxylic acid ethyl ester.

m. 2-Diethylamino-3-phenyl-6-methyl-4-(2'-trifluoromethylphenyl)-4H-pyrane-5-carboxylic acid ethyl ester.

n. 2-Diethylamino-3,6-dimethyl-4-(2'-naphthyl)-4 H-pyrane-5-carboxylicacid isopropyl ester.

o. 2-Diethylamino-3,6-dimethyl-4-(4'-quinolyl)-4 H-pyrane-5-carboxylicacid ethyl ester.

p. 2-Diethylamino-3-ethyl-6-methyl-4(3,4,5-trimethoxyphenyl)-4H-pyrane-5-carboxylic acid allyl ester.

The compounds of the present invention have demonstrated the followingpharmacological activity in animal tests:

1. On parenteral, oral and perlingual administration the compounds ofthe present invention produce a distinct and long-lasting dilation ofthe coronary vessels. This action on the coronary vessels is intensifiedby a simultaneous nitrile-like effect of reducing the load on the heart.The compounds influence or modify the heart metabolism in the sense ofan energy saving.

2. The compounds of the present invention lower the blood pressure ofnormotonic and hypertonic animals and can thus be used as antipertensiveagents.

3. The excitability of the stimulus formation and excitation conductionsystem within the heart is lowered so that an antifibrillation actiondemonstrable at therapeutic doses results.

4. The tone of the smooth muscle of the vessels is greatly reduced underthe action of the compounds of the present invention. Thisvascular-spasmolytic action can take place in the entire vascular systemor can manifest itself more or less isolated in circumscribed vascularregions (such as, for example, the central nervous system).

5. The compounds of the present invention have stronglymuscular-spasmolytic actions which manifest themselves on the smoothmuscle of the stomach, of the intestinal tract, of the urogenital tractand of the respiratory system.

6. The compounds of she present invention influence the cholesterollevel and liquid level of the blood.

The compounds of the present invention may also be formulated intopharmaceutical compositions. The pharmaceutical compositions of thepresent invention contain a major or minor amount, e.g. from 99.5 to0.1%, preferably 90 to 0.5%, of the active agent as herein defined incombination with a pharmaceutical carrier, the carrier comprising one ormore solid, semi-solid or liquid diluent, filler and formulationadjuvant which is non-toxic, inert and pharmaceutically acceptable. Suchpharmaceutical compositions are preferably in dosage unit form; i.e.physically discrete units containing a predetermined amount of the drugcorresponding to a fraction or multiple of the dose which is calculatedto produce the desired therapeutic response. The dosage units cancontain one, two, three, four or more single doses or, alternatively,one half, third or fourth of a single dose. A single dose preferablycontains an amount sufficient to produce the desired therapeutic effectupon administration at one application at one or more dosage unitsaccording to a predetermined dosage regimen, usually a whole, half,third, or quarter of the daily dosage administered once, twice, three orfour times a day. Other therapeutic agents can also be present.

Although the dosage and dosage regimen must in each case be carefullyadjusted, utilizing sound professional judgement and considering theage, weight and condition of the recipient, the route of administrationand the nature and gravity of the illness, generally the dosage forintravenal administration will be from 0.25 mg to 900 mg, preferably 1to 450 mg. The preferred oral administration is 5 mg to 45 g, preferably50 mg to 2.7 g. In each case, the dosage represents the amount of activeingredients to be administered. The daily dosage on i.v. administrationis preferably 0.005 mg/kg to 10 mg/kg, particularly 0.02 to 5 mg/kg, andfor oral administration is 0.1 to 50 mg/kg, particularly 1 to 30 mg/kg.In some instances a sufficient therapeutic effect can be obtained at alower dose while in others, a larger dose will be required.

Oral administration can be effected utilizing solid and liquid dosageunit forms such as powders, tablets, dragees, capsules, granulates,suspensions, solutions and the like.

Powders are prepared by comminuting the compound to a suitable fine sizeand mixing with a similarly comminuted pharmaceutical carrier such as anedible carbohydrate as for example starch, lactose, sucrose, glucose ormannitol. Sweetening, flavoring, preservative, dispersing and coloringagents can also be present.

Capsules are made by preparing a powder mixture as described above andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagaragar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally with a binder such as carboxymethyl cellulose analginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste, acacia mucilage or solutions of cellulosic orpolymeric materials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the resulting imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet-formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Themedicaments can also be combined with free-flowing, inert carriers andcompressed into tablets directly without going through the granulatingor slugging steps. A clear or opaque protective coating consisting of asealing coat of shellac, a coating of sugar or polymeric material and apolish coating of wax can be provided. Dyestuffs can be added to thesecoatings to distinguish different unit dosages.

Oral fluids such as solutions, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous sucrose solution while elixirsare prepared through the use of non-toxic alcoholic vehicle. Suspensionscan be formulated by dispersing the compound in a non-toxic vehicle.Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols andpolyoxyethylene sorbitol esters, preservatives, flavor additives such aspeppermint oil or saccharin, and the like, can also be added.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

Parenteral administration can be effected utilizing liquid dosage unitforms such as sterile solutions and suspensions intended forsubcutaneous, intramuscular or intravenous injection. These are preparedby suspending or dissolving a measured amount of the compound in anon-toxic liquid vehicle suitable for injection such as an aqueous oroleaginous medium and sterilizing the suspension or solution.Alternatively, a measured amount of the compound is placed in a vial andthe vial and its contents are sterilized and sealed. An accompanyingvial or vehicle can be provided for mixing prior to administration.Non-toxic salts and salt solutions can be added to render the injectionisotonic. Stabilizers, preservatives and emulsifiers can also be added.

Rectal administration can be effected utilizing suppositories in whichthe compound is admixed with low-melting, water-soluble or insolublesolids such as polyethylene glycol, cocoa butter, higher esters as, forexample, myristyl palmitate, or mixtures thereof.

Topical administration can be effected utilizing solid dosage unit formssuch as powders or liquid or semiliquid dosage unit forms such assolutions, suspensions, ointments, pastes, creams and gels. The powdersare formulated utilizing such carriers as talc, bentonite, silicic acid,polyamide powder and the like. Liquid and semiliquid formulations canutilize such carriers, in addition to those described above, aspolyethylene glycol, vegetable and mineral oils, alcohols such asisopropanol and the like. Other excipients such as emulsifiers,preservatives, colorants, perfumes and the like can also be present.Formulations can also be administered as an aerosol, utilizing the usualpropellants such as the chlorofluorohydrocarbons. Oral and intravenouscompositions are preferred.

The coronary action of compounds representative of those of the presentinvention is set forth below in Table I:

                  Table I                                                         ______________________________________                                                  Distinctly discernible rise in the oxygen saturation in the                   coronary sinus                                                      Compound of Dose                                                              Preparative (mg/kg body weight                                                                           Duration of                                        Example No. intravenously) Action                                             ______________________________________                                        1           0.5            90 mins                                            4           0.5            30 mins                                            6           5.0            20 mins                                            ______________________________________                                    

The coronary action set out in Table I was ascertained on narcotizedheart-catheterized mongrel dogs by measuring the rise in oxygensaturation in the coronary sinus.

The antihypertensive effect of compounds representative of those of thepresent invention as indicated by their blood-pressure-lowering effectis shown in Table II below. The dose quoted in the 3rd column is thedose required to lower the blood pressure of hypertensive rats by atleast 15 mm Hg.

                  Table II                                                        ______________________________________                                                                  Lowering of blood                                               Toxicity in   pressure in high                                    Compound of mice, mg/kg   blood pressure rats,                                Preparative administered  mg/kg administered                                  Example No. orally        orally                                              ______________________________________                                        1                         from 1.0                                            7                         from 3.0                                            9                         from 3.0                                            ______________________________________                                    

The following nonlimitative examples more particularly describe thepresent invention:

EXAMPLE 1 ##SPC7##

After heating a solution of 26.3 g of 3'-nitrobenzylideneacetoaceticacid ethyl ester, 11.3 g of cyanoacetic acid ethyl ester and 2 ml ofpiperidine in 100 ml of ethanol for 4 hours, 2-amino-6 -methyl-4-(3'-nitrophenyl)-4H-pyrane-3,5 -dicarboxylic acid diethyl ester ofmelting point 161°C (ethanol) was obtained. Yield 63% of theory.

EXAMPLE 2 ##SPC8##

11.1 g of 1-diethylaminoprop-1-ine are added to a solution of 25.2 g of2'-chlorobenzylideneacetoacetic acid ethyl ester in 100 ml of toluene.After the first exothermic reaction, the mixture is boiled for 4 hoursunder reflux and the residue is distilled: Boiling point at 0.9 mm. Hg:205°C. 2-Diethylamino-3,6 -dimethyl-4(2'-chlorophenyl)-4H-pyrane-5-carboxylic acid ethyl ester. Yield 76% of theory.

EXAMPLE 3 ##SPC9##

A solution of 15.6 g of ethylideneacetoacetic acid ethyl ester and 11.1g of diethylaminoprop-1-ine is heated for 4 hours after the firstvigorous reaction. The mixture is concentrated and the residue isdistilled: Boiling point at 0.6 mm. Hg: 112°-126°C. 2-Diethylamino-3,4,6-trimethyl-4, H-pyrane-5-carboxylic acid ethyl ester. Yield 66% oftheory.

EXAMPLE 4 ##SPC10##

After boiling a solution of 24.9 g of 3'-nitrobenzylideneacetoaceticacid methyl ester, 11.3 g of cyanoacetic acid ethyl ester and 2 ml ofpiperidine in 100 ml of ethanol for 4 hours,2-amino-6-methyl-4-(3'-nitrophenyl)-4 H-pyrane-3,5 -dicarboxylic acid3-ethyl ester-5-methyl ester of melting point 134°C was obtained. Yield67% of theory.

EXAMPLE 5 ##SPC11##

A solution of 28.6 g of 2'-trifluoromethylbenzylideneacetoacetic acidethyl ester and 11.1 g of 1-diethylaminopro-p-1-ine in 200 ml of tolueneis boiled for 4 hours under reflux after the first vigorous reaction.The mixture is concentrated and the residue is distilled: Boiling pointat 0.1 mm. Hg: 139°-146°C. 2-Diethylamino-3,6-dimethyl-4-(2'-trifluoromethylphenyl)-4 H-pyrane-5-carboxylic acidethyl ester. Yield 59% of theory.

EXAMPLE 6 ##SPC12##

A solution of 23.2 g of 2'-methylbenzylideneacetoacetic acid ethyl esterand 11.1 g of 1-diethylaminoprop-1-ine in 150 ml of toluene is boiledfor 4 hours under reflux after the first vigorous reaction. The mixtureis concentrated and the residue distilled: Boiling point at 0.4 mm. Hg:163°-174°C. 2-Diethylamino-3,6 -dimethyl-4-(2'-methylphenyl)-4H-pyrane-5-carboxylic acid ethyl ester.

EXAMPLE 7 ##SPC13##

After heating a solution of 27.7 g of 3'-nitrobenzylideneacetoaceticacid isopropyl ester, 11.3 g of cyanoacetic acid ethyl ester and 2 ml ofpiperidine in 100 ml of ethanol for 4 hours,2-amino-6-methyl-4-(3'-nitrophenyl)-4 H-pyrane-3,5 -dicarboxylic acid3-ethyl ester-5-isopropyl ester of melting point 135°C (ethanol) wasobtained. Yield 46% of theory.

EXAMPLE 8 ##SPC14##

A solution of 21.8 g of benzylideneacetoacetic acid ethyl ester and 11.1g of 1-diethylaminoprop-1-ine in 150 ml of toluene is boiled for 4 hoursunder reflux after the first vigorous reaction. The mixture isconcentrated and the residue is distilled: Boiling point at 0.2 mm. Hg:142°-155°C. 2-Diethylamino-3,6 -dimethyl-4-phenyl-4H-pyrane-5-carboxylic acid ethyl ester. Yield 62% of theory.

EXAMPLE 9 ##SPC15##

On heating a solution of 23.3 g of 3'-nitrobenzylideneacetylacetone,11.3 g of cyanoacetic acid ethyl ester and 2 ml of piperidine in 100 mlof ethanol for 4 hours, 2-amino-5-acetyl-6 -methyl-4-(3'-nitrophenyl)-4H-pyrane-3-carboxylic acid ethyl ester of melting point 181°C (ethanol)was obtained. Yield 51% of theory.

EXAMPLE 10 ##SPC16##

A solution of 24.8 g of 2'-methoxybenzylideneacetoacetic acid ethylester and 11.1 g of 1-diethylaminoprop-1-ine in 150 ml of toluene wasboiled for 4 hours under reflux after the first vigorous reaction. Themixture is concentrated and the residue is distilled: Boiling point at0.3 mm. Hg: 164°-168°C. 2-Diethylamino-3,6-dimethyl-4-(2'-methoxyphenyl)-4 H-pyrane-5-carboxylic acid ethyl ester.Yield 64% of theory.

EXAMPLE 11 ##SPC17##

On heating a solution of 28.4 g of3'-nitro-6'-chlorobenzylideneacetoacetic acid methyl ester, 11.4 g ofcyanoacetic acid ethyl ester and 2 ml of piperidine in 100 ml of ethanolfor 4 hours, 2-amino-6-methyl-4-(3'-nitro-6'-chlorophenyl)-4H-pryane-3,5 -dicarboxylic acid 3-ethyl ester-5-methyl ester of meltingpoint 159°C was obtained. Yield 42% of theory.

EXAMPLE 12 ##SPC18##

A solution of 21.0 g of 2'-furfurylideneacetoacetic acid ethyl ester and11.1 g of 1-diethylaminoprop-1-ine in 150 ml of toluene was boiled for 4hours under reflux after the first vigorous reaction. The mixture isconcentrated and the residue is distilled: Boiling point at 0.8 mm. Hg:159°-167°C. 2-Diethylamino-3,6 -dimethyl-4-(2'-furyl)-4H-pryane-5-carboxylic acid ethyl ester.

EXAMPLE 13 ##SPC19##

11.1 g of 1-diethylaminoprop-1-ine are added to a solution of 26.8 g of(1'-naphthylidene)-acetoacetic acid ethyl ester in 100 ml of toluene.After the first exothermic reaction, the mixture is boiled for 4 hoursunder reflux and the residue is distilled: Boiling point at 215 mm. Hg:210°-222°C. 2-Diethylamino-3,6 -dimethyl-4-(1'-naphthyl)-4H-pyrane-5-carboxylic acid ethyl ester. Yield: 38% of theory.

EXAMPLE 14 ##SPC20##

11.1 g of 1-diethylaminoprop-1-ine are added to a solution of 22.4 g of(2'-thenylidene)-acetoacetic acid ethyl ester in 100 ml of toluene.After the first exothermic reaction, the mixture is boiled for 4 hoursunder reflux and the residue is distilled: Boiling point at 2 mm. Hg:184°-189°C. 2-Diethylamino-3,6 -dimethyl-4-(2'-thenyl)-4H-pyrane-5-carboxylic acid ethyl ester. Yield: 59% of theory.

EXAMPLE 15 ##SPC21##

11.1 g of 1-diethylaminoprop-1-ine are added to a solution of 24.3 g of2'-cyanobenzylideneacetoacetic acid ethyl ester in 100 ml of toluene.After the first exothermic reaction, the mixture is boiled for 4 hoursunder reflux and the residue is distilled: Boiling point at 2 mm. Hg:188°-192°C. 2-Diethylamino-3,6 -dimethyl-4-(2'-cyanophenyl)-4H-pyrane-5-carboxylic acid ethyl ester. Yield 46% of theory.

EXAMPLE 16 ##SPC22##

11.1 g of 1-diethylaminoprop-1-ine are added to a solution of 29.0 g of3'-ethoxycarbonylbenzylideneacetoacetic acid ethyl ester in 100 ml oftoluene. After the first exothermic reaction, the mixture is boiled for4 hours under reflux and the residue is distilled: Boiling point at 1.3mm Hg: 213°-217°C. 2-Diethylamino-3,6-dimethyl-4-(3'-ethoxycarbonyl-phenyl)-4 H-pyrane-5-carboxylic acidethyl ester. Yield: 41% of theory.

What is claimed is:
 1. A pharmaceutical composition useful for effectingvasodilating action in humans and animals and for treating hypertensionin humans and animals which comprises a vasodilating amount or anantihypertensive amount of a compound of the formula ##SPC23##wherein R¹and R² are the same or different and are each hydrogen or straight- orbranched-chain lower alkyl; R³ is straight- or branched-chain loweralkyl, phenyl or --COOR' wherein R' is straight, branched or cycliclower alkyl, lower alkenyl or lower alkynyl; R⁴ is phenyl unsubstitutedor substituted by 1, 2 or 3 of the same or different substituentsselected from the group consisting of lower alkyl, lower alkoxy,halogen, nitro, cyano, trifluoromethyl, carb(lower alkoxy) and --SO_(n)lower alkyl wherein n is 0, 1 or 2, or naphthyl; R⁵ is straight,branched or cyclic lower alkyl or --OR" wherein R" is straight, branchedor cyclic lower alkyl, lower alkenyl or lower alkynyl or straight,branched or cyclic lower alkyl, lower alkenyl or lower alkynylsubstituted by 1 or 2 oxygen atoms; and R⁶ is hydrogen or lower alkyl,incombination with a pharmaceutically acceptable nontoxic inert diluent orcarrier.
 2. A composition according to claim 1 whereinR¹ and R² are thesame or different and each are alkyl of 1 to 4 carbon atoms; R³ isstraight- or branched-chain alkyl of 1 to 4 carbon atoms, phenyl or--COOR' wherein R' is straight- or branched-chain alkyl of 1 to 5 carbonatoms, straight- or branched-chain alkenyl of 2 to 5 carbon atoms,straight- or branched-chain alkynyl of 2 to 5 carbon atoms, cycloalkylof 3 to 5 carbon atoms, or cycloalkenyl of 3 to 5 carbon atoms; R⁴ isphenyl unsubstituted or substituted or substituted by 1 or 2 of the sameor different substituents selected from the group consisting of alkyl of1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen, nitro,cyano, trifluoromethyl, carbalkoxy of 1 to 4 carbon atoms in the alkoxymoiety and --SO_(n) alkyl wherein the alkyl moiety is of 1 to 4 carbonatoms and n is 0 or 2, or naphthyl; R⁵ is straight- or branched-chainalkyl of 1 to 4 carbon atoms or --OR" wherein R" is straight- orbranched-chain alkyl of 1 to 4 carbon atoms, straight- or branched-chainalkenyl of 2 to 5 carbon atoms, straight- or branched-chain alkynyl of 2to 5 carbon atoms, cycloalkyl of 3 to 5 carbon atoms, cycloalkenyl of 3to 5 carbon atoms, or straight- or branched-chain alkyl of 1 to 5 carbonatoms or alkenyl of 2 to 5 carbon atoms interrupted by 1 oxygen atom;and R⁶ is hydrogen or alkyl of 1 to 4 carbon atoms.
 3. A compositionaccording to claim 1 whereinR¹ and R² are the same or different and eachare hydrogen, methyl or ethyl; R³ is methyl, ethyl, phenyl or --COOR'wherein R' is methyl, ethyl or allyl; R⁴ is phenyl unsubstituted orsubstituted by nitro, cyano, trifluoromethyl, chloro, methyl,carbethoxy, 1 to 3 methoxy moieties, nitro and methoxy, nitro andtrifluoromethyl, nitro and thiomethyl, or nitro and chloro, or R⁴ isnaphthyl; R⁵ is --OR" wherein R" is methyl, ethyl, propyl, allyl orcyclohexyl; and R⁶ is methyl or ethyl.
 4. A composition according toclaim 1 whereinR¹ and R² are the same or different and each arehydrogen, methyl or ethyl; R³ is methyl, carbomethoxy, or carbethoxy; R⁴is phenyl, unsubstituted or substituted by nitro, chloro,trifluoromethyl, methyl, methoxy, cyano, carbethoxy or nitro and chloro;or R⁴ is naphthyl; R⁵ is methoxy, ethoxy, or propoxy; and R⁶ is methyl.5. The composition according to claim 1 wherein the compound is2-amino-6-methyl-4-(2'-nitrophenyl)-4 H-pyrane-3,5-dicarboxylic aciddiethyl ester.
 6. The composition according to claim 1 wherein thecompound is 2-amino-6-methyl-4-(2'-nitrophenyl)-4H-pyrane-3,5-dicarboxylic acid 3-ethyl ester 5-methyl ester.
 7. Thecomposition according to claim 1 wherein the compound is2-amino-6-ethyl-4-(3'-nitrophenyl)-4 H-pyrane-3,5-dicarboxylic aciddiethyl ester.
 8. The composition according to claim 1 wherein thecompound is 2-amino-6-methyl-4-(3'-nitro-6'-methoxyphenyl)-4H-pyrane-3,5-dicarboxylic acid diethyl ester.
 9. The compositionaccording to claim 1 wherein the compound is2-amino-6-methyl-4-(2'-trifluoromethyl-4'-nitrophenyl)-4H-pyrane-3,5-dicarboxylic acid 3-ethyl ester-5-methyl ester.
 10. Thecomposition according to claim 1 wherein the compound is2-amino-6-methyl-4-(3'-nitro-6'-methylmercaptophenyl)-3,5-dicarboxylicacid dimethyl ester.
 11. The composition according to claim 1 whereinthe compound is 2-amino-6-methyl-4-(3'-cyanophenyl)-4H-pyrane-3,5-dicarboxylic acid 3-allyl ester-5 ethyl ester.
 12. Thecomposition according to claim 1 wherein the compound is2-amino-6-methyl-4-(3'-nitrophenyl)-4 H-pyrane-3,5-dicarboxylic acid3-ethyl ester-5-cyclohexyl ester.
 13. The composition according to claim1 wherein the compound is2-dimethylamino-3-methyl-6-ethyl-4-(3'-carbethoxyphenyl)-4H-pyrane-5-carboxylic acid ethyl ester.
 14. The composition according toclaim 1 wherein the compound is2-dimethylamino-3-methyl-6-ethyl-4-(2'-cyanophenyl)-4H-pyrane-5-carboxylic acid ethyl ester.
 15. The composition according toclaim 1 wherein the compound is2-diethylamino-3-phenyl-6-methyl-4-(2'-trifluoromethylphenyl)-4H-pyrane-5-carboxylic acid ethyl ester.
 16. The composition according toclaim 1 wherein the compound is2-diethylamino-3,6-dimethyl-4-(2'-naphthyl)-4 H-pyrane-5-carboxylic acidisopropyl ester.
 17. The composition according to claim 1 wherein thecompound is 2-diethylamino-3-ethyl-6-methyl-4-(3,4,5-trimethoxyphenyl)-4H-pyrane-5-carboxylic acid allyl ester.
 18. The composition according toclaim 1 wherein the compound is ##SPC24##
 19. The composition accordingto claim 1 wherein the compound is ##SPC25##
 20. The compositionaccording to claim 1 wherein the compound is ##SPC26##
 21. Thecomposition according to claim 1 wherein the compound is ##SPC27## 22.The composition according to claim 1 wherein the compound is ##SPC28##23. The composition according to claim 1 wherein the compound is##SPC29##
 24. The composition according to claim 1 wherein the compoundis ##SPC30##
 25. The composition according to claim 1 wherein thecompound is ##SPC31##
 26. The composition according to claim 1 whereinthe compound is ##SPC32##
 27. The composition according to claim 1wherein the compound is ##SPC33##
 28. The composition according to claim1 wherein the compound is ##SPC34##
 29. The composition according toclaim 1 wherein the compound is ##SPC35##
 30. The composition accordingto claim 1 wherein the compound is ##SPC36##
 31. A composition accordingto claim 1 in oral administration form.
 32. A composition according toclaim 1 in parenteral administration form.
 33. A method of producingvasodilating action in humans and animals and a method of treatinghypertension in humans and animals which comprises administering to suchhuman or animal a vasodilating amount or an anti-hypertensive amount ofa compound of the formula: ##SPC37##wherein R¹ and R² are the same ordifferent and are each hydrogen or straight- or branched-chain loweralkyl; R³ is straight- or branched-chain lower alkyl, phenyl or --COOR'wherein R' is straight, branched or cyclic lower alkyl, lower alkenyl orlower alkynyl; R⁴ is phenyl unsubstituted or substituted by 1, 2 or 3 ofthe same or different substituents selected from the group consisting oflower alkyl, lower alkoxy, halogen, nitro, cyano, trifluoromethyl,carb(lower alkoxy) and --SO_(n) lower alkyl wherein n is 0, 1 or 2, ornaphthyl; R⁵ is straight, branched or cyclic lower alkyl or --OR"wherein R" is straight, branched or cyclic lower alkyl, lower alkenyl orlower alkynyl or straight, branched or cyclic lower alkyl, lower alkenylor lower alkynyl substituted by 1 or 2 oxygen atoms; and R⁶ is hydrogenor lower alkyl.
 34. A method according to claim 33 whereinR¹ and R² arethe same or different and each are alkyl or 1 to 4 carbon atoms; R³ isstraight- or branched-chain alkyl of 1 to 4 carbon atoms, phenyl or--COOR' wherein R' is straight- or branched-chain alkyl of 1 to 5 carbonatoms, straight- or branched-chain alkenyl of 2 to 5 carbon atoms,straight- or branched-chain alkynyl of 2 to 5 carbon atoms, cycloalkylof 3 to 5 carbon atoms, or cycloalkenyl of 3 to 5 carbon atoms; R⁴ isphenyl unsubstituted or substituted or substituted by 1 or 2 of the sameor different substituents selected from the group consisting of alkyl of1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen, nitro,cyano, trifluoromethyl, carbalkoxy of 1 to 4 carbon atoms in the alkoxymoiety and --SO_(n) alkyl wherein the alkyl moiety is of 1 to 4 carbonatoms and n is 0 or 2, or naphthyl; R⁵ is straight- or branched-chainalkyl of 1 to 4 carbon atoms or --OR" where R" is straight- orbranched-chain alkyl of 1 to 4 carbon atoms, straight- or branched-chainalkenyl of 2 to 5 carbon atoms, straight- or branched-chain alkynyl of 2to 5 carbon atoms, cycloalkyl of 3 to 5 carbon atoms, cycloalkenyl of 3to 5 carbon atoms, or straight- or branched-chain alkyl of 1 to 5 carbonatoms or alkenyl of 2 to 5 carbon atoms interrupted by 1 oxygen atom;and R⁶ is hydrogen or alkyl of 1 to 4 carbon atoms.
 35. A methodaccording to claim 33 whereinR¹ and R² are the same or different andeach are hydrogen, methyl or ethyl; R³ is methyl, ethyl, phenyl or--COOR' wherein R' is methyl, ethyl or allyl; R⁴ is phenyl unsubstitutedor substituted by nitro, cyano, trifluoromethyl, chloro, methyl,carbethoxy, 1 to 3 methoxy moieties, nitro and methoxy, nitro andtrifluoromethyl, nitro and thiomethyl, or nitro and chloro, or R⁴ isnaphthyl; R⁵ is --OR" wherein R" is methyl, ethyl, propyl, allyl orcyclohexyl; and R⁶ is methyl or ethyl.
 36. A method according to claim33 whereinR¹ and R² are the same or different and each are hydrogen,methyl or ethyl; R³ is methyl, carbomethoxy, or carbethoxy; R⁴ isphenyl, unsubstituted or substituted by nitro, chloro, trifluoromethyl,methyl, methoxy, cyano, carbethoxy or nitro and chloro; or R⁴ isnaphthyl; R⁵ is methoxy, ethoxy, or propoxy; and R⁶ is methyl.
 37. Themethod according to claim 33 wherein the compound is2-amino-6-methyl-4-(2'-nitrophenyl)-4 H-pyrane-3,5-dicarboxylic aciddiethyl ester.
 38. The method according to claim 33 wherein the compoundis 2-amino-6-methyl-4-(2'-nitrophenyl)-4 H-pyrane-3,5-dicarboxylic acid3-ethyl ester 5-methyl ester.
 39. The method according to claim 33wherein the compound is 2-amino-6-ethyl-4-(3'-nitrophenyl)-4H-pyrane-3,5-dicarboxylic acid diethyl ester.
 40. The method accordingto claim 33 wherein the compound is2-amino-6-methyl-4-(3'-nitro-6'-methoxyphenyl)-4H-pyrane-3,5-dicarboxylic acid diethyl ester.
 41. The method accordingto claim 33 wherein the compound is2-amino-6-methyl-4-(2'-trifluoromethyl-4'-nitrophenyl)-4H-pyrane-3,4-dicarboxylic acid 3-ethyl ester-5-methyl ester.
 42. Themethod according to claim 33 wherein the compound is2-amino-6-methyl-4-(3'-nitro-6'-methylmercaptophenyl)-3,5-dicarboxylicacid dimethyl ester.
 43. The method according to claim 33 wherein thecompound is 2-amino-6-methyl-4-(3'-cyanophenyl)-4H-pyrane-3,5-dicarboxylic acid 3-allyl ester-5-ethyl ester.
 44. Themethod according to claim 33 wherein the compound is2-amino-6-methyl-4-(3'-nitrophenyl)-4 H-pyrane-3,5-dicarboxylic acid3-ethyl ester-5-cyclohexyl ester.
 45. The method according to claim 33wherein the compound is2-dimethylamino-3-methyl-6-ethyl-4-(3'-carbethoxyphenyl)-4H-pyrane-5-carboxylic acid ethyl ester.
 46. The method according toclaim 33 wherein the compound is2-dimethylamino-3-methyl-6-ethyl-4-(2'-cyanophenyl)-4H-pyrane-5-carboxylic acid ethyl ester.
 47. The method according toclaim 33 wherein the compound is2-diethylamino-3-phenyl-6-methyl-4-(2'-trifluoromethylphenyl)-4H-pyrane-5-carboxylic acid ethyl ester.
 48. The method according toclaim 33 wherein the compound is2-diethylamino-3,6-dimethyl-4-(2'-naphthyl)-4 H-pyrane-5-carboxylic acidisopropyl ester.
 49. The method according to claim 33 wherein thecompound is 2-diethylamino-3-ethyl-6-methyl-4-(3,4,5-trimethoxyphenyl)-4H-pyrane-5-carboxylic acid allyl ester.
 50. The method according toclaim 33 wherein the compound is ##SPC38##
 51. The method according toclaim 33 wherein the compound is ##SPC39##
 52. The method according toclaim 33 wherein the compound is ##SPC40##
 53. The method according toclaim 33 wherein the compound is ##SPC41##
 54. The method according toclaim 33 wherein the compound is ##SPC42##
 55. The method according toclaim 33 wherein the compound is ##SPC43##
 56. The method according toclaim 33 wherein the compound is ##SPC44##
 57. The method according toclaim 33 wherein the compound is ##SPC45##
 58. The method acording toclaim 33 wherein the compound is ##SPC46##
 59. The method according toclaim 33 wherein the compound is ##SPC47##
 60. The method according toclaim 33 wherein the compound is ##SPC48##
 61. The method according toclaim 33 wherein the compound is ##SPC49##
 62. The method according toclaim 33 wherein the compound is ##SPC50##
 63. A method according toclaim 33 wherein the administration is oral.
 64. A method according toclaim 33 wherein the administration is parenteral.